The disposition and metabolism of ¹⁴C-oxprenolol·HCl in man

Abstract

1. The disposition and metabolism of oxprenolol have been investigated in two healthy male volunteers, following a single 160 mg oral dose of racemic ¹⁴C-labelled oxprenolol.

2. Absorption was rapid and complete. Peak blood concentrations of total radioactivity were 8.83 and 8.21 nmol.g⁻¹ after 1 and 1.5 h in the two subjects. After 4 days 93.4 and 81.90% of the dose was excreted in urine, and a total of 96.6 and 84.5% found in the excreta.

3. Mean peak blood concentrations of unchanged R(+)—and S(—)—oxprenolol were 0.83 and 0.81 nmol.g⁻¹. Maximal concentrations of the glucuronides of the R(+)—and S(—)—isomers were 1.98 and 3.51 nmol.g⁻¹. The mean half-lives of both oxprenolol enantiomers were 1.8 h, those of their glucuronides were 3.2h (R(+)) and 4.6h (S(—)).

4. Unchanged oxprenolol and the oxprenolol glucuronides constituted 11.4 and 66.5% of the area under the blood concentration-time curve (AUC, 0–24 h) of total radioactivity. The AUC-ratio of R(+) to S(—) was 1.19 for free oxprenolol and 0–36 for the glucuronides. Free metabolites II-X represented together 4.3% of ¹⁴C-AUC, and their glucuronides 15.2%.

5. In urine, 1.8 and 1.0% of the total radioactivity was present as unchanged R(+)—and S(—)—oxprenolol, respectively. The glucuronides of the enantiomers accounted for 24.5 and 26.5%. The percentages of free 4- and 5- hydroxy oxprenolol were 0.7 and 2.4% while those of their glucuronides were 12.3 and 7.5%. Metabolites IV-X constituted together 6.2% in free form and 5.3% in conjugated form.

6. In conclusion, the good mass balances in blood and urine has enabled the comprehensive and quantitative description of the metabolic fate of oxprenolol in man. Oxprenolol is extensively metabolized, direct O-glucuronidation being the major metabolic pathway and oxidative reactions minor ones. The disposition of the oxprenolol enantiomers revealed no remarkable stereoselective differences.